Digoxin is a cardiac glycoside known for use in the treatment of congestive heart failure and, when administered at the proper therapeutic dosage level, exerts a direct cardiotonic action on the myocardium to increase the force of contraction and improve cardiac tone. While the proper dosage level may vary considerably from patient to patient, the therapeutic dosage range is nevertheless quite low when compared with most other drugs. Moreover, the ratio between toxic and effective doses may also be relatively low. For example, it has been reported that a 50 percent change in the steady-state plasma concentration of digoxin may bring a patient into either the subtherapeutic or toxic concentration range. G. Levy et al, Circulation, Vol. 49, pp. 391-394, March 1974. The need to assure the adequate bioavailability of digoxin products is therefore readily apparent.
A further clinical problem arises because a digoxin tablet may contain a correct dose of the drug but provide only a portion of that dose for absorption by the patient. Incomplete absorption occurs if a digoxin tablet dissolves relatively slowly in the gastrointestinal fluids, and it has been found that the dissolution rate of digoxin tablets varies considerably from brand to brand and (for the same brand) from batch to batch. Such variations in dissolution rate lead to marked differences in the plasma digoxin levels and clinical response achieved during maintenance digoxin therapy. T. R. D. Shaw, American Heart Journal, Vol. 87, No. 3, pp. 399-401, March 1974.
The problem is still further complicated by the relatively low dosage of tablet formulations (a typical tablet dosage falls within the range of 0.125 to 0.5 milligrams) since even slight variations in the distribution of digoxin during a tableting operation may result in significant differences in the dosage levels of digoxin in the same batch or successive batches of tablets.
While it is known that when digoxin is administered orally as a solution absorption is nearly complete, users commonly reject liquid preparations in favor of tablets because of the far greater convenience in carrying, storing, and administering the drug in solid form. Therefore, despite the variations in bioavailability and therapeutic response of digoxin in the solid state, and indications of poor content uniformity from tablet to tablet and/or lot to lot, tablet formulations of digoxin constitute the primary form in which the drug is marketed and used.
While it might be thought that an encapsulated form of digoxin in solution might overcome the aforementioned problems, digoxin is insoluble in water and is known to be soluble only in solutions (such as dilute alcohol) which also dissolve gelatin capsules. Consequently, the only recognized choices for preparing digoxin in therapeutic dosage form are as a solid (i.e., tablets, powders, crystals) or as a liquid to be dispensed in measured amounts from a bottle or other container.